Mutant mice with reduced NMDA-NR1 glycine affinity or lack of D-amino acid oxidase function exhibit altered anxiety-like behaviors.
Several compounds that promote activation of the N-methyl-d-aspartate receptor (NMDAR) glycine site have been proposed as treatments for schizophrenia, but the impact of these putative antipsychotics on anxiety remains unclear. In this study, we employed genetic and pharmacological mouse models of altered NMDAR glycine site function to examine the effects of these proposed treatments in unconditioned tests of anxiety. In the elevated plus-maze, open field, and novel object test, homozygous Grin1(D481N) mutant mice that have a five-fold reduction in NMDAR glycine affinity demonstrated an anxiolytic-like phenotype. In contrast, d-serine, a direct activator of the NMDAR glycine site, and ALX-5407, a glycine transporter-1 (GlyT-1) inhibitor, enhanced anxiety-like behaviors in wild-type and Grin1(D481N) mutant animals. Homozygous Dao1(G181R) mutant mice that lack function of the d-serine catabolic enzyme, d-amino acid oxidase (DAO), displayed an elevation in anxiety. Deficient DAO activity also reversed the anxiolytic effects of diminished NMDAR function in mice carrying both the homozygous Grin1(D481N) and Dao1(G181R) mutation. Thus, a direct agonist of the NMDAR glycine site, a GlyT-1 inhibitor, and suppression of DAO function induced anxiogenic-like behaviors. Consequently, application of these treatments for amelioration of schizophrenic symptoms necessitates caution as an enhancement of comorbid anxiety disorders may result.
Labrie
Viviane
V
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Ave., Toronto, ON, Canada M5G 1X5. labrie@mshri.on.ca
Clapcote
Steven J
SJ
Roder
John C
JC
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001007:Anxiety / Q000235:genetics* / Q000523:psychology*; D002352:Carrier Proteins / Q000235:genetics; D003605:D-Amino-Acid Oxidase / Q000378:metabolism*; D005260:Female; D005998:Glycine / Q000378:metabolism*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009154:Mutation / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*; D012521:Sarcosine / Q000031:analogs & derivatives / Q000494:pharmacology; D012694:Serine / Q000494:pharmacology; D012919:Social Behavior; D013028:Space Perception / Q000187:drug effects
C510369:(R)-(N-(3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl))sarcosine; D014150:Antipsychotic Agents; D002352:Carrier Proteins; C121673:Gprin1 protein, mouse; C409466:NR1 NMDA receptor; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D012694:Serine; D003605:D-Amino-Acid Oxidase; D005998:Glycine; D012521:Sarcosine